An estimated 4 million Americans are infected with hepatitis C virus (HCV). Epidemiological studies have shown that HCV infection is frequently associated with type 2 diabetes mellitus, but a cause-and-effect relationship has not been established. Diabetes and insulin resistance are of critical importance to liver disease and have been linked to accelerated hepatitis C liver fibrosis progression. We believe there may be a causal link between HCV and diabetes, and we propose herein to investigate potential mechanisms of glucose intolerance in the setting of HCV that may elucidate this causal relationship. By identifying the mechanism(s) by which HCV promotes glucose intolerance, we hope to stimulate efforts to develop specific treatments for patients at risk of developing diabetes. Type 2 diabetes is characterized by insulin resistance and the failure of pancreatic B-cells to appropriately compensate by enhancing insulin output. Studies using surrogate measures of insulin sensitivity have suggested a possible increase in insulin resistance in HCV. Given that insulin resistance by itself does not result in hyperglycemia, we hypothesize that HCV impairs B-cell function and compensatory hyperinsulinemia in predisposed individuals with insulin resistance, and that impairment in B-cell function may be HCV genotype-dependent. We further hypothesize that insulin-sensitive glycolytic disposal of glucose by peripheral tissue - a major component of glucose homeostasis - is reduced by HCV infection. In order to test these hypotheses, we propose 3 specific aims: Aim 1: To determine whether insulin secretion (relative to insulin sensitivity) is decreased in patients with HCV infection compared to patients with hepatitis B (HBV) infection; Aim 2: To investigate whether insulin secretion is reduced more significantly in patients with HCV genotype 1 than in patients with genotype 2 or 3; Aim 3: To determine whether whole-body glycolytic disposal of glucose is reduced in HCV patients. Using a cohort of HCV-infected individuals and HBV-infected controls, we will employ specific dynamic methodologies to measure insulin secretory function in relation to insulin resistance and whole-body glycolytic disposal of glucose. Additionally, we will assess the impact of host and viral factors that may be important in glucose intolerance. We anticipate that insulin secretory function and whole-body glycolytic disposal of glucose will be impaired in HCV patients. The proposed studies will provide insight into the pathogenesis of diabetes in the setting of HCV because we will be able to directly evaluate alterations in glucose metabolism induced by HCV [unreadable] [unreadable]